Muscle–Brain Crosstalk and Neuroimmune Regulation in Post- Intensive Care Syndrome (PICS): Implications for Exercise Mimetics

Post-Intensive Care Syndrome (PICS) is characterized by persistent muscle weakness, depression, and cognitive impairment that continue after discharge from the intensive care unit. In older adults, these symptoms often interact with and exacerbate sarcopenia. Recent work has highlighted disruption of immune homeostasis within the central nervous system—particularly the sustained activation of microglia—as a key contributor to neuropsychiatric manifestations of PICS. However, the peripheral signals that trigger and maintain these changes remain poorly understood. In this seminar, drawing on findings from a PICS model that combines acute lung injury with immobilization, we explore the molecular pathology of PICS from the perspective of disrupted neuroimmune regulation originating in skeletal muscle. Even after apparent recovery from the acute phase, persistent skeletal muscle atrophy and low-grade systemic inflammation were accompanied by microglial activation and altered neuroinflammatory signaling in the brain, which were suggested to be associated with depressive-like behavior and cognitive decline. Focusing on apelin—a myokine induced by physical exercise—our analyses indicate that reduced apelin signaling is linked to PICS-like phenotypes and microglial activation, whereas restoration of this pathway may ameliorate neurobehavioral abnormalities. These findings suggest that exercise mimetics represented by apelin could serve as molecular interventions that re-tune the neuroimmune environment, offering therapeutic potential for PICS and age-related sarcopenia, particularly in patients for whom physical exercise is difficult. Furthermore, we will discuss emerging modes of inter-organ communication, including extracellular vesicles (EVs), as a molecular basis through which muscle-derived signals regulate microglial function. We propose reframing PICS as a disorder of neuroimmune regulation and outline future research directions centered on EV-omics.